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January - March 2018: 
Volume 31, Issue 1

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Pneumon 2018, 31(1):11-13
Non Tuberculous Mycobacterial Infection From Oscar Wilde to Gene Sequencing
Authors Information
1First Academic Department of Pneumonology, Interstitial Lung Diseases Unit, Hospital for Diseases  of the Chest, “Sotiria”, Medical School,  National and Kapodistrian University  of Athens, Athens, Greece
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A 70-year old female, lifetime non-smoker was admitted to our outpatient clinic complaining of mild productive cough, dyspnea on exertion and general fatigue. During the last ten years she reported multiple lower respiratory tract infections and was diagnosed with bronchiectasis based on compatible HRCT findings 5 years ago. Four years ago, Pseudomonas Aeruginosa was isolated from her sputum and was treated with oral ciprofloxacin for 21 days. During the last three years she reported no hospitalizations and was self-prescribing antibiotics during worsening of her symptoms.

On admission she was afebrile, thin and pthysic and had mild kyphoscoliosis. Her clinical examination revealed: SaO2: 95%, (FiO2: 21%), heart rate: 90 bpm, respiratory rate: 12/min, and inspiratory squeaks on auscultation, mainly localized on lower lobes. She had no clubbing or ankle edema. She reported no Raynaud’s phenomenon or other symptoms of arthritis (arthralgias, morning stiffness) or myositis. Her high resolution computed tomography revealed multiple cystic bronchiectases and nodular tree-in-bud opacities (Figure 1). A complete etiologic investigation of non-cystic fibrosis bronchiectasis was performed.

Figure 1. High-resolution chest computed tomography shows extensive bronchiectatic lesions and tree-in-bud opacities with linear branching pattern and nearly uniform distribution in the right middle and lower lobe, as well as the lingula and the left lower lobe, indicating architectural distortion and terminal airway mucous impaction with adjacent peribronchiolar inflammation. Insets are showing bronchiectatic lesions and tree-in-bud opacities (left panels and right upper panel) as well as signet-ring shaped bronchiectasis (right lower panel).
 

The patient was immunocompetent based on quantitative serum immunoglobulin and general blood tests, revealed no history compatible with pertussis infection at infancy or childhood and her serum immunologic profile was negative. She was HIV and hepatitis B and C negative. Her tuberculin skin test was 8 mm and the interferon-gamma release assay (IGRA-QuantiferonTB-gold) was negative. Her sputum smears (n=3), PCR assays and solid-medium (Lowenstein Jensen) culture were negative for mycobacterium tuberculosis (MTB). Solid medium cultures of sputum specimens revealed colonies of non-tuberculous mycobacterium avium complex (MAC). She was commenced treatment with a thrice-weekly regimen consisted of: rifampicin – 600 mg (qid), clarithromycin - 1000 mg (bid) and ethambutol-1000 mgr (qid). Two months later the patient reported significant improvement of her dyspnea, fatigue and cough as well as sputum purulence and volume.

The isolation of non-tuberculous mycobacterial (NTM) remains a clinical dilemma. Because NTM naturally exist in the environment, isolation of NTM from a non-sterile respiratory specimen does not necessary mean infection. NTM pulmonary infection develops commonly in structural lung disease such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, pneumonoconiosis, prior tuberculosis, pulmonary alveolar proteinosis and esophageal motility disorders1. In addition, clinicians should be highly aware and raise suspicion for NTM infection in cases of recurrent respiratory infections in immunocompetent individuals with radiological features of bronchiectasis.

More than 20 years ago, NTM pulmonary infection has been described in the context of Lady Windermere’s syndromewhich typically consists of the phenotype of a thin, well-mannered elderly woman with voluntarily cough suppression, mainly middle-lobe bronchiectasis and pulmonary mycobacterium avium complex infection2,3.  The fastidious nature and reticence to expectorate are believed to be the main predisposing factors for lung infection by allowing secretions to collect into airways, particularly in the right middle lobe which has the longest and narrowest structure among lobar bronchi. The name originates from the lead character in Oscar Wilde’s play Lady Windermere’s Fan, which satirizes the strict morals and polite manners typical of the Victorian era in Great Britain.

The diagnosis of NTM pulmonary infection can be challenging and to this end clinicians should integrate atypical respiratory symptoms (cough, sputum, dyspnea) and radiological features (cylindrical bronchiectasis, multifocal tree-in bud opacities or cavitary lesions) to highly specific microbiological findings (positive culture for NTM in more than 2 expectorated sputum specimens or one specimen from bronchial lavage or washing) (Table 1)4. It is important to note that AFB stains (Kinyoun method seems to be superior to Ziehl-Neelsen) cannot distinguish between NTM and MTB. Nucleic acid amplification (NAA) tests are needed. Culture remains the gold standard for confirmation of NTM diagnosis. Culture media are similar to MTB. Both solid (Lowenstein Jensen) and liquid culture (Middlebrook 7H9) platforms are required. Nevertheless, since treatment and outcomes are different among NTM species, precise NTM identification is critical. Sequencing of the 16sRNA gene is the reference method of choice for NTM discrimination up to the subspecies level. Gene sequencing can also be used to identify Inducible macrolide resistance, especially in mycobacteria with rapidly growing taxonomy, such as M. abscessus complex4.

Macrolides represent the cornerstone of NTM-MAC treatment (Table 1). Management can be difficult and lengthy (at least 12 months) and should be individually tailored based on the NTM species, disease symptoms, radiological extent and patients’ preferences1. On the other hand, current guidelines suggest similar to MTB therapeutic regimens (except for pyrazinamide) for the treatment of M. Kansasii, which is a relatively treatable pathogen. The therapy for M. Abscessus still remains a bottleneck for physicians and researchers. Guidelines suggest an oral macrolide and two parenteral agents such as amikacin, imipenem, tygecycline, cefoxitin and linezolid for several months. Bedaquiline, tigecycline, linezolid and clofazimine (an anti-leprosy drug) represent therapeutic agents used for MDR-TB infections5-9.

In NTM refractory cases, debulking surgery of the most affected area of the lung may be helpful in selected number of patients10. In general, except from M. Kansasii, NTM infection is difficult to eradicate with anti-microbial therapy alone and is characterized by frequent relapses. Clinical trials enrolling patients with refractory NTM infection are sorely needed. Multiple combination therapies involving both surgical and anti-microbial interventions with novel therapeutic agents may hold promise for the future. Early referral to a reference center of excellence and multidisciplinary approaches are mandatory for optimal therapeutic decisions.

Table 1. Diagnostic Criteria and Therapeutic Approach for Non Tuberculous Mycobacterial (NTM)- MAC (Mycobacterium Avium complex) lung Disease
 

References

References

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2.  Ballard DH, Previgliano CH. Lady Windermere Syndrome. Am J Med Sci 2016; 351:e7.

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9.  Wallace RJ, Jr., Brown-Elliott BA, Crist CJ, Mann L, Wilson RW. Comparison of the in vitro activity of the glycylcycline tigecycline (formerly GAR-936) with those of tetracycline, minocycline, and doxycycline against isolates of nontuberculous mycobacteria. Antimicrob Agents Chemother 2002; 46:3164-7.

10.  Mitchell JD. Surgical approach to pulmonary nontuberculous mycobacterial infections. Clin Chest Med 2015; 36:117-22.